Invasive brain interventions often result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain Barrier (BBB) protects the brain tissue from foreign molecules. Laboratory experiments and first clinical trials have shown that focused ultrasound (FUS) beams can be used for noninvasive interventions. However, the utilization of FUS in the brain has been seriously limited by the difficulty of delivering ultrasound through the skull bone. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered noninvasively through an intact skull. This hypothesis has now been validated in three clinical studies that demonstrate that brain tissue can be noninvasively coagulated in the central part of the brain. During the current grant period, we furthered our initial research and developed methods to enhance FUS interaction with tissue using microbubbles, thus making whole brain sonications feasible. We have further studied the impact of ultrasound exposures on brain tissue and demonstrated chemotherapy delivery across the BBB. We, and others, have used animal tumor models to demonstrate that chemotherapy treatment significantly increases animal survival when combined with FUS induced BBB disruption. We have also developed computer simulation programs, control technology and treatment methods that will improve the delivery of ultrasound energy. Our study plan is to extend our current research and further explore the feasibility of using intravascular microbubbles to enhance the trans-skull sonications. Our goals are: First, to use our prototype phased array ultrasound system with passive acoustic monitoring to provide acoustic signal feedback, and thus localize and control bubble- enhanced treatments. Second, to utilize our computer models to develop more precise focusing, using higher and multiple frequency sonications, such that the focal volume size is reduced. This will provide better control and allow nonuniform brain tissue to be adequately exposed. Third, to construct and test the new arrays designed using the computer simulations. Fourth, to perform in vivo two-photon microscopy and behavior studies to increase our understanding of ultrasound induced BBB disruption effects on delicate brain regions. Finally, to further test the effectiveness of the ultrasound-induced BBB disruption for the delivery of chemotherapeutic agents and natural killer cells for the treatment o malignant brain tumors, and the delivery of siRNA for the treatment of Huntington's disease. Our vision is that successful trans-skull delivery of FUS could have a major impact on the treatment of many brain disorders. If successful, this research will have a major impact on patient care.